Delivery of rizatriptan or zolmitriptan through an inhalation route

ABSTRACT

The present invention relates to the delivery of headache and anti-migraine compounds through an inhalation route. Specifically, it relates to aerosols containing that are used in inhalation therapy. In a method aspect of the present invention, rizatriptan or zolmitriptan is administered to a patient through an inhalation route. The method comprises: a) heating a composition, comprising rizatriptan or zolmitriptan to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol with less than  5 % of the drug degradation products. In a kit aspect of the present invention, a kit for delivering rizatriptan or zolmitriptan through an inhalation route is provided which comprises: a) a thin coating of a rizatriptan or zolmitriptan composition; and, b) a device for dispending said thin coating as a condensation aerosol.

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/155,621, entitled “Delivery of Rizatriptan or ZolmitriptanThrough an Inhalation Route,” filed May 22, 2002, Hale, Rabinowitz,Solas, and Zaffaroni; which claims priority to U.S. provisionalapplication Ser. No. 60/294,203 entitled “Thermal Vapor Delivery ofDrugs,” filed May 24, 2001, Rabinowitz and Zaffaroni; to U.S.provisional application Ser. No. 60/317,479 entitled “Aerosol DrugDelivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni; U.S.provisional application Ser. No. 60/332,280 entitled “Delivery ofRizatriptan or Zolmitriptan Through an Inhalation Route,” filed Nov. 21,2001, Rabinowitz and Hale; and to U.S. provisional application Ser. No.60/336,218 entitled “Delivery of Rizatriptan or Zolmitriptan Through anInhalation Route,” filed Oct. 30, 2001, Rabinowitz and Hale; the entiredisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery of rizatriptan orzolmitriptan through an inhalation route. Specifically, it relates toaerosols containing rizatriptan or zolmitriptan that are used ininhalation therapy.

BACKGROUND OF THE INVENTION

[0003] There are a number of compositions currently marketed for thetreatment of migraine headaches. The compositions contain at least oneactive ingredient that provides for observed therapeutic effects. Amongthe active ingredients given in such anti-migraine compositions arerizatriptan and zolmitriptan.

[0004] It is desirable to provide a new route of administration forrizatriptan and zolmitriptan that rapidly produces peak plasmaconcentrations of the compounds. The provision of such a route is anobject of the present invention.

SUMMARY OF THE INVENTION

[0005] New routes of administration for the compounds may increase therate at which their peak plasma concentrations are reached. Such routesare provided herein.

[0006] The present invention relates to the delivery of rizatriptan orzolmitriptan through an inhalation route. Specifically, it relates toaerosols containing rizatritpan or zolmitriptan that are used ininhalation therapy.

[0007] In a composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight ofrizatriptan or zolmitriptan. Preferably, the particles comprise at least10 percent by weight of rizatriptan or zolmitriptan. More preferably,the particles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent or 99.97 percent by weight ofrizatriptan or zolmitriptan.

[0008] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0009] Typically, the particles comprise less than 10 percent by weightof rizatriptan or zolmitriptan degradation products. Preferably, theparticles comprise less than 5 percent by weight of rizatriptan orzolmitriptan degradation products. More preferably, the particlescomprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight ofrizatriptan or zolmitriptan degradation products.

[0010] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0011] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0012] Typically, where the particles comprise rizatriptan, theparticles comprise less than 5 percent by weight of rizatriptan N-oxide(C₁₅H₁₉N₅O, MW of 285.34). Preferably, the particles comprise less than2.5 percent by weight of rizatriptan N-oxide. More preferably, theparticles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight ofrizatriptan N-oxide.

[0013] Typically, where the particles comprise rizatriptan, theparticles comprise less than 5 percent by weight of didehydrorizatriptan (removal of H₂, C₁₅H₁₇N₅, MW of 267.33). Preferably, theparticles comprise less than 2.5 percent by weight of didehydrorizatriptan. More preferably, the particles comprise less than 1, 0.5,0.1 or 0.03 percent by weight of didehydro rizatriptan.

[0014] Typically, where the particles comprise zolmitriptan, theparticles comprise less than 5 percent by weight of zolmitriptanN-oxide. Preferably, the particles comprise less than 2.5 percent byweight of zolmitriptan N-oxide. More preferably, the particles compriseless than 1, 0.5, 0.1 or 0.03 percent by weight of zolmitriptan N-oxide.

[0015] Typically, where the particles comprise zolmitriptan, theparticles comprise less than 5 percent by weight of didehydrozolmitriptan. Preferably, the particles comprise less than 2.5 percentby weight of didehydro zolmitriptan. More preferably, the particlescomprise less than 1, 0.5, 0.1 or 0.03 percent by weight of didehydrozolmitriptan.

[0016] Typically, the aerosol has an inhalable aerosol drug mass densityof between 0.25 mg/L and 40 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 20 mg/L.More preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.5 mg/L and 10 mg/L.

[0017] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

[0018] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0019] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.0.

[0020] Typically, the aerosol is formed by heating a compositioncontaining rizatriptan or zolmitriptan to form a vapor and subsequentlyallowing the vapor to condense into an aerosol.

[0021] In another composition aspect of the present invention, a doseform of an antimigraine compound is provided for the treatment ofmigraine, wherein the dose form comprises less than the typical oraldose of the antimigraine compound.

[0022] Typically, where the antimigraine compound is rizatriptan, thedose form comprises less than 4 mg of rizatriptan. Preferably, the doseform comprises less than 3.5 mg of rizatriptan. More preferably, thedose form comprises less than 3.0 or 2.5 mg of rizatriptan.

[0023] Typically, where the antimigraine compound is zolmitriptan, thedose form comprises less than 1 mg of zolmitriptan. Preferably, the doseform comprises less than 0.75 mg of zolmitriptan. More preferably, thedose form comprises less than 0.5 mg of zolmitriptan.

[0024] Typically, the dose form further comprises less than 90 percentby weight of water. Preferably, the dose form further comprises lessthan 80 percent by weight of water. More preferably, the dose formfurther comprises less than 70 percent, 60 percent, 50 percent, 40percent, 30 percent, 20 percent, or 10 percent by weight of water.

[0025] Typically, the dose form further comprises less than 90 percentby weight of a pharmaceutically acceptable excipient. Preferably, thedose form further comprises less than 80 percent by weight of apharmaceutically acceptable excipient. More preferably, the dose formfurther comprises less than 70 percent, 60 percent, 50 percent, 40percent, 30 percent, 20 percent, or 10 percent by weight of apharmaceutically acceptable excipient.

[0026] In a method aspect of the present invention, either rizatriptanor zolmitriptan is delivered to a mammal through an inhalation route.The method comprises: a) heating a composition, wherein the compositioncomprises at least 5 percent by weight of rizatriptan or zolmitriptan,to form a vapor; and, b) allowing the vapor to cool, thereby forming acondensation aerosol comprising particles, which is inhaled by themammal. Preferably, the composition that is heated comprises at least 10percent by weight of rizatriptan or zolmitriptan. More preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of rizatriptan or zolmitriptan.

[0027] Typically, the particles comprise at least 5 percent by weight ofrizatriptan or zolmitriptan. Preferably, the particles comprise at least10 percent by weight of rizatriptan or zolmitriptan. More preferably,the particles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of rizatritpan or zolmitriptan.

[0028] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0029] Typically, the particles comprise less than 10 percent by weightof rizatriptan or zolmitriptan degradation products. Preferably, theparticles comprise less than 5 percent by weight of rizatriptan orzolmitriptan degradation products. More preferably, the particlescomprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of rizatriptan orzolmitriptan degradation products.

[0030] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent water.

[0031] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0032] Typically, where the particles comprise rizatriptan, theparticles comprise less than 5 percent by weight of rizatriptan N-oxide(C₁₅H₁₉N₅O, MW of 285.34). Preferably, the particles comprise less than2.5 percent by weight of rizatriptan N-oxide. More preferably, theparticles comprise less than 1, 0.5, 0.1 or 0.03 percent by weight ofrizatriptan N-oxide.

[0033] Typically, where the particles comprise rizatriptan, theparticles comprise less than 5 percent by weight of didehydrorizatriptan (removal of H₂, C₁₅H₁₇N₅,MW of 267.33). Preferably, theparticles comprise less than 2.5 percent by weight of didehydrorizatriptan. More preferably, the particles comprise less than 1, 0.5,0.1 or 0.03 percent by weight of didehydro rizatriptan.

[0034] Typically, where the particles comprise zolmitriptan, theparticles comprise less than 5 percent by weight of zolmitriptanN-oxide. Preferably, the particles comprise less than 2.5 percent byweight of zolmitriptan N-oxide. More preferably, the particles compriseless than 1, 0.5, 0.1 or 0.03 percent by weight of zolmitriptan N-oxide.

[0035] Typically, where the particles comprise zolmitriptan, theparticles comprise less than 5 percent by weight of didehydrozolmitriptan. Preferably, the particles comprise less than 2.5 percentby weight of didehydro zolmitriptan. More preferably, the particlescomprise less than 1, 0.5, 0.1 or 0.03 percent by weight of didehydrozolmitriptan.

[0036] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0037] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.0.

[0038] Typically, the delivered aerosol has an inhaleable aerosol drugmass density of between 0.25 mg/L and 40 mg/L. Preferably, the aerosolhas an inhaleable drug mass density of between 0.5 mg/L and 20 mg/L.More preferably, the aerosol has an inhalable drug mass density ofbetween 0.5 mg/L and 10 mg/L.

[0039] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0040] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhaleable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhaleable particles per second.

[0041] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0042] Typically, where the condensation aerosol comprises rizatriptan,between 1 mg and 20 mg of rizatriptan are delivered to the mammal in asingle inspiration. Preferably, between 1.5 mg and 15 mg of rizatriptanare delivered to the mammal in a single inspiration. More preferably,between 2 mg and 10 mg of rizatriptan are delivered to the mammal in asingle inspiration.

[0043] Typically, where the condensation aerosol comprises zolmitriptan,between 0.5 mg and 10 mg of zolmitriptan are delivered to the mammal ina single inspiration. Preferably, between 1.5 mg and 7.5 mg ofzolmitriptan are delivered to the mammal in a single inspiration. Morepreferably, between 2 mg and 5 mg of zolmitriptan are delivered to themammal in a single inspiration.

[0044] Typically, the delivered condensation aerosol results in a peakplasma concentration of rizatriptan or zolmitriptan in the mammal inless than 1 h. Preferably, the peak plasma concentration is reached inless than 0.5 h. More preferably, the peak plasma concentration isreached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterialmeasurement).

[0045] Typically, the delivered condensation aerosol is used to treatmigraine.

[0046] Typically, where the condensation aerosol comprises rizatriptan,less than 4 mg of rizatriptan is inhaled by the mammal in a 2 hourperiod. Preferably, less than 3.5 mg of rizatriptan is inhaled by themammal in a 2 hour period. More preferably, less than 3.0 or 2.5 mg ofrizatriptan is inhaled by the mammal in a 2 hour period.

[0047] Typically, where the condensation aerosol comprises zolmitriptan,less than 1 mg of zolmitriptan is inhaled by the mammal in a 2 hourperiod. Preferably, less than 0.75 mg of zolmitriptan is inhaled by themammal in a 2 hour period. More preferably, less than 0.5 mg ofzolmitriptan is inhaled by the mammal in a 2 hour period.

[0048] In another method aspect of the present invention, a method oftreating migraine is provided which comprises administering a dose of anantimigraine compound to a mammal that is less than the typical oraldose.

[0049] Typically, where the antimigraine compound is rizatriptan, lessthan 4 mg of rizatriptan is administered to the mammal in any 2 hourperiod. Preferably, less than 3.5 mg of rizatriptan is administered tothe mammal in any 2 hour period. More preferably, less than 3.0 mg or2.5 mg of rizatriptan is administered to the mammal in any 2 hourperiod.

[0050] Typically, where the antimigraine compound is zolmitriptan, lessthan 1 mg of zolmitriptan is administered to the mammal in any 2 hourperiod. Preferably, less than 0.75 mg of zolmitriptan is administered tothe mammal in any 2 hour period. More preferably, less than 0.5 mg ofzolmitriptan is administered to the mammal in any 2 hour period.

[0051] In a kit aspect of the present invention, a kit for deliveringrizatriptan or zolmitriptan through an inhalation route to a mammal isprovided which comprises: a) a composition comprising at least 5 percentby weight of rizatriptan and zolmitriptan; and, b) a device that forms arizatriptan or zolmitriptan aerosol from the composition, for inhalationby the mammal. Preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of rizatriptan or zolmitriptan.

[0052] Typically, the device contained in the kit comprises: a) anelement for heating the rizatriptan or zolmitriptan composition to forma vapor; b) an element allowing the vapor to cool to form an aerosol;and, c) an element permitting the mammal to inhale the aerosol.

[0053] Typically, where the kit comprises rizatriptan, it comprises lessthan 4 mg of rizatriptan. Preferably, the kit comprises less than 3.5 mgof rizatriptan. More preferably, it comprises less than 3 mg or 2.5 mgof rizatriptan.

[0054] Typically, where the kit comprises zolmitriptan, it comprisesless than 1 mg of zolmitriptan. Preferably, the kit comprises less than0.75 mg of zolmitriptan. More preferably, it comprises less than 0.5 mgof zolmitriptan.

BRIEF DESCRIPTION OF THE FIGURE

[0055]FIG. 1 shows a cross-sectional view of a device used to deliverrizatriptan or zolmitriptan containing aerosols to a mammal through aninhalation route.

DETAILED DESCRIPTION OF THE INVENTION

[0056] Definitions

[0057] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0058] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0059] “Aerosol drug mass density” refers to the mass of rizatriptan orzolmitriptan per unit volume of aerosol.

[0060] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0061] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0062] “Amorphous particle” refers to a particle that does not contain.more than 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

[0063] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0064] “Inhalable aerosol drug mass density” refers to the aerosol drugmass density produced by an inhalation device and delivered into atypical patient tidal volume.

[0065] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0066] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0067] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0068] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0069] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0070] “Rate of drug aerosol formation” refers to the mass ofaerosolized rizatriptan or zolmitriptan produced by an inhalation deviceper unit time.

[0071] “Rizatriptan” refers toN,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine,which has an empirical formula of C₁₅H₁₉N₅. The compound is a free basewith a molecular weight of 269.4 g/m.

[0072] “Rizatriptan degradation product” refers to a compound resultingfrom a chemical modification of rizatriptan. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation (e.g.,N-oxide formation), elimination (e.g., E₁ and E₂ reaction pathways) anddimerization.

[0073] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0074] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0075] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0076] “Zolmitriptan” refers to(S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone,which has an empirical formula of C₁₆H₂₁N₃O₂. The compound is a freebase with a molecular weight of 287.36 g/m.

[0077] “Zolmitriptan degradation product” refers to a compound resultingfrom a chemical modification of zolmitriptan. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation (e.g.,N-oxide formation), elimination (e.g., E₁ and E₂ reaction pathways) anddimerization.

[0078] Obtaining Rizatriptan or Zolmitriptan

[0079] Rizatriptan and zolmitriptan are either isolated fromcommercially available products or synthesized. To isolate rizatriptan,MAXALT® Tablets are dissolved in water and treated with base to formrizatriptan free base. The free base is extracted with diethyl ether toafford rizatriptan. Zolmitriptan is isolated by dissolving ZOMIG®Tablets in water and extracting the aqueous solution with diethyl etherand dichloromethane.

[0080] Synthetic routes to both rizatriptan and zolmitriptan are wellknown. U.S. Pat. No. 5,298,520, for instance, describes the synthesis ofrizatriptan. The synthesis of zolmitriptan is reported in U.S. Pat. No.5,399,574.

[0081] Formation of Rizatriptan or Zolmitriptan Containing Aerosols

[0082] Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising rizatriptan or zolmitriptan to form a vapor, followed bycooling of the vapor such that it condenses to provide a rizatriptan orzolmitriptan comprising aerosol (condensation aerosol). The compositionis heated in one of four forms: as pure active compound (i.e., purerizatriptan or zolmitriptan); as a mixture of active compound and apharmaceutically acceptable excipient; as a salt form of the pure activecompound; and, as a mixture of active compound salt form and apharmaceutically acceptable excipient.

[0083] Salt forms of rizatriptan or zolmitriptan are either commerciallyavailable or are obtained from the corresponding free base using wellknown methods in the art. A variety of pharmaceutically acceptable saltsare suitable for aerosolization. Such salts include, without limitation,the following: hydrochloric acid, hydrobromic acid, acetic acid, maleicacid, formic acid, and fumaric acid salts.

[0084] Pharmaceutically acceptable excipients may be volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with rizatriptan or zolmitriptan.Classes of such excipients are known in the art and include, withoutlimitation, gaseous, supercritical fluid, liquid and solid solvents. Thefollowing is a list of exemplary carriers within the classes: water;terpenes, such as menthol; alcohols, such as ethanol, propylene glycol,glycerol and other similar alcohols; dimethylformamide;dimethylacetamide; wax; supercritical carbon dioxide; dry ice; andmixtures thereof.

[0085] Solid supports on which the composition is heated are of avariety of shapes. Examples of such shapes include, without limitation,cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mmthickness and virtually any shape permeated by small (e.g., less than1.0 mm-sized) pores. Preferably, solid supports provide a large surfaceto volume ratio (e.g., greater than 100 per meter) and a large surfaceto mass ratio (e.g., greater than 1 cm² per gram).

[0086] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0087] A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0088] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yams and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0089] The heating of the rizatriptan or zolmitriptan compositions isperformed using any suitable method. Examples of methods by which heatcan be generated include the following: passage of current through anelectrical resistance element; absorption of electromagnetic radiation,such as microwave or laser light; and, exothermic chemical reactions,such as exothermic solvation, hydration of pyrophoric materials andoxidation of combustible materials.

[0090] Delivery of Rizatriptan or Zolmitriptan Containing Aerosols

[0091] Rizatriptan or zolmitriptan containing aerosols of the presentinvention are delivered to a mammal using an inhalation device. Wherethe aerosol is a condensation aerosol, the device has at least threeelements: an element for heating a rizatriptan or zolmitriptancontaining composition to form a vapor; an element allowing the vapor tocool, thereby providing a condensation aerosol; and, an elementpermitting the mammal to inhale the aerosol. Various suitable heatingmethods are described above. The element that allows cooling is, in itsimplest form, an inert passageway linking the heating means to theinhalation means. The element permitting inhalation is an aerosol exitportal that forms a connection between the cooling element and themammal's respiratory system.

[0092] One device used to deliver the rizatriptan or zolmitriptancontaining aerosol is described in reference to FIG. 1. Delivery device100 has a proximal end 102 and a distal end 104, a heating module 106, apower source 108, and a mouthpiece 110. A rizatriptan or zolmitriptancomposition is deposited on a surface 112 of heating module 106. Uponactivation of a user activated switch 114, power source 108 initiatesheating of heating module 106 (e.g, through ignition of combustible fuelor passage of current through a resistive heating element). Therizatriptan or zolmitriptan composition volatilizes due to the heatingof heating module 106 and condenses to form a condensation aerosol priorto reaching the mouthpiece 110 at the proximal end of the device 102.Air flow travelling from the device distal end 104 to the mouthpiece 110carries the condensation aerosol to the mouthpiece 110, where it isinhaled by the mammal.

[0093] Devices, if desired, contain a variety of components tofacilitate the delivery of rizatriptan or zolmitriptan containingaerosols. For instance, the device may include any component known inthe art to control the timing of drug aerosolization relative toinhalation (e.g., breath-actuation), to provide feedback to patients onthe rate and/or volume of inhalation, to prevent excessive use (i.e.,“lock-out” feature), to prevent use by unauthorized individuals, and/orto record dosing histories.

[0094] Dosage of Rizatriptan or Zolmitriptan Containing Aerosols

[0095] Rizatriptan and zolmitriptan are given orally at strengths of 5mg or 10 mg and 2.5 mg or 5 mg respectively for the treatment ofmigraine. As aerosols, 0.5 mg to 15 mg of rizatriptan and 0.25 mg to 7.5mg of zolmitriptan are generally provided per inspiration for the sameindication. A typical dosage of a rizatriptan or zolmitriptan aerosol iseither administered as a single inhalation or as a series of inhalationstaken within an hour or less (dosage equals sum of inhaled amounts).Where the drug is administered as a series of inhalations, a differentamount may be delivered in each inhalation. The dosage amount ofrizatriptan or zolmitriptan in aerosol form is generally no greater thantwice the standard dose of the drug given orally.

[0096] One can determine the appropriate dose of rizatriptan orzolmitriptan containing aerosols to treat a particular condition usingmethods such as animal experiments and a dose-finding (Phase I/II)clinical trial. One animal experiment involves measuring plasmaconcentrations of drug in an animal after its exposure to the aerosol.Mammals such as dogs or primates are typically used in such studies,since their respiratory systems are similar to that of a human. Initialdose levels for testing in humans is generally less than or equal to thedose in the mammal model that resulted in plasma drug levels associatedwith a therapeutic effect in humans. Dose escalation in humans is thenperformed, until either an optimal therapeutic response is obtained or adose-limiting toxicity is encountered.

[0097] Analysis of Rizatriptan or Zolmitriptan Containing Aerosols

[0098] Purity of a rizatriptan or zolmitriptan containing aerosol isdetermined using a number of methods, examples of which are described inSekine et al., Journal of Forensic Science 32:1271-1280 (1987) andMartin et al., Journal of Analytic Toxicology 13:158-162 (1989). Onemethod involves forming the aerosol in a device through which a gas flow(e.g., air flow) is maintained, generally at a rate between 0.4 and 60L/min. The gas flow carries the aerosol into one or more traps. Afterisolation from the trap, the aerosol is subjected to an analyticaltechnique, such as gas or liquid chromatography, that permits adetermination of composition purity.

[0099] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0100] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofrizatriptan or zolmitriptan degradation products.

[0101] Particle size distribution of a rizatriptan or zolmitriptancontaining aerosol is determined using any suitable method in the art(e.g., cascade impaction). An Andersen Eight Stage Non-viable CascadeImpactor (Andersen Instruments, Smyrna, Ga.) linked to a furnace tube bya mock throat (USP throat, Andersen Instruments, Smyrna, Ga.) is onesystem used for cascade impaction studies.

[0102] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0103] Inhalable aerosol drug mass density is determined, for example,by delivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

[0104] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*(φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

[0105] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

[0106] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice. The delivery is for a set period of time (e.g., 3 s), and themass of particulate matter collected is determined by weighing theconfined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0107] Rate of drug aerosol formation is determined, for example, bydelivering a rizatriptan or zolmitriptan containing aerosol into aconfined chamber via an inhalation device over a set period of time(e.g., 3 s). Where the aerosol is pure rizatriptan or zolmitriptan, theamount of drug collected in the chamber is measured as described above.The rate of drug aerosol formation is equal to the amount of rizatriptanor zolmitriptan collected in the chamber divided by the duration of thecollection time. Where the rizatriptan or zolmitriptan containingaerosol comprises a pharmaceutically acceptable excipient, multiplyingthe rate of aerosol formation by the percentage of rizatriptan orzolmitriptan in the aerosol provides the rate of drug aerosol formation.

[0108] Utility of Rizatriptan or Zolmitriptan Containing Aerosols

[0109] Rizatriptan and Zolmitriptan are selective 5HT₁ subtype agonists.Such compounds exhibit vasoconstrictor activity and are used for thetreatment of headache. Examples of headaches that are treated byadministration of rizatriptan or zolmitriptan include migraine, clusterheadache, chronic paroyxysmal hemicrania, headache associated withvascular disorders, tension headaches and pediatric migraine.

[0110] The following examples are meant to illustrate, rather thanlimit, the present invention.

EXAMPLE 1 Isolation of Rizatriptan

[0111] To 10 mL of water was added 9 MAXALT® Tablets, each containing 10mg of rizatriptan. After the tablets dissolved, 1N NaOH was added to thesolution until it became basic (pH 11-12). The aqueous solution wasextracted six times with diethyl ether. The combined ether extracts weredried (Na₂SO₄), filtered and concentrated on a rotary evaporator toprovide 88 mg (98% recovery) of rizatriptan.

EXAMPLE 2 Volatilization of Rizatriptan

[0112] A solution of 10 mg rizatriptan in 1 mL diethyl ether was spreadout in a thin layer on a 10 cm×15 cm sheet of aluminum foil. The diethylether was allowed to evaporate. The coated aluminum foil sheet wasinserted into a glass tube in a furnace (tube furnace). A glass woolplug was placed in the tube adjacent to the foil sheet, and an air flowof 2 L/min was applied. The furnace was heated to 250° C. for 30 s tovolatilize the coated rizatriptan and then was allowed to cool. Theglass wool was extracted, and HPLC analysis of the collected materialshowed it to be at least 99% pure rizatriptan.

EXAMPLE 3 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Rizatriptan Aerosol

[0113] A solution of 11.3 mg rizatriptan in 200 μL dichloromethane wasspread out in a thin layer on the central portion of a 4 cm×9 cm sheetof aluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. One of the openings of the tube wassealed with a rubber stopper, another was loosely covered with the endof the halogen tube, and the third was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within 1 s, an aerosol appearedand was drawn into the 1 L flask by use of the piston, with collectionof the aerosol terminated after 7 s. The aerosol was analyzed byconnecting the 1 L flask to an eight-stage Andersen non-viable cascadeimpactor. Results are shown in table 1. MMAD of the collected aerosolwas 1.2 microns with a geometric standard deviation of 1.7. Also shownin table 1 is the number of particles collected on the various stages ofthe cascade impactor, given by the mass collected on the stage dividedby the mass of a typical particle trapped on that stage. The mass of asingle particle of diameter D is given by the volume of the particle,πD³/6, multiplied by the density of the drug (taken to be 1 g/cm³). Theinhalable aerosol particle density is the sum of the numbers ofparticles collected on impactor stages 3 to 8 divided by the collectionvolume of 1 L, giving an inhalable aerosol particle density of 3×10⁷particles/mL. The rate of inhalable aerosol particle formation is thesum of the numbers of particles collected on impactor stages 3 through 8divided by the formation time of 7 s, giving a rate of inhalable aerosolparticle formation of 5×10⁹ particles/second. TABLE 1 Determination ofthe characteristics of a rizatriptan condensation aerosol by cascadeimpaction using an Andersen 8-stage non-viable cascade impactor run at 1cubic foot per minute air flow. Particle size Average particle Masscollected Number of Stage range (microns) size (microns) (mg) particles0  9.0-10.0 9.5 0.0 0 1 5.8-9.0 7.4 0.0 0 2 4.7-5.8  5.25 0.1 1.3 × 10⁶3 3.3-4.7 4.0 0.2 6.0 × 10⁶ 4 2.1-3.3 2.7 0.4 3.9 × 10⁷ 5 1.1-2.1 1.61.2 5.6 × 10⁸ 6 0.7-1.1 0.9 1.0 2.6 × 10⁹ 7 0.4-0.7  0.55 0.5 5.7 × 10⁹8   0-0.4 0.2 0.1  2.4 × 10¹⁰

EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofRizatriptan Aerosol

[0114] A solution of 11.6 mg rizatriptan in 200 μL dichloromethane wasspread out in a thin layer on the central portion of a 4 cm×9 cm sheetof aluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. One of the openings of the tube wassealed with a rubber stopper, another was loosely covered with the endof the halogen tube, and the third was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within seconds, an aerosolappeared and was drawn into the 1 L flask by use of the piston, withformation of the aerosol terminated after 7 s. The aerosol was allowedto sediment onto the walls of the 1 L flask for approximately 30minutes. The flask was then extracted with dichloromethane and theextract analyzed by HPLC with detection by light absorption at 225 nm.Comparison with standards containing known amounts of rizatriptanrevealed that 3.2 mg of >99% pure rizatriptan had been collected in theflask, resulting in an aerosol drug mass density of 3.2 mg/L. Thealuminum foil upon which the rizatriptan had previously been coated wasweighed following the experiment. Of the 11.6 mg originally coated onthe aluminum, all of the material was found to have aerosolized in the 7s time period, implying a rate of drug aerosol formation of 1.7 mg/s.

EXAMPLE 5 Isolation of Zolmitriptan

[0115] To water was added 17 ZOMIG® Tablets, each containing 5 mg ofzolmitriptan. The resulting milky solution was extracted three timeswith diethyl ether and three times with dichloromethane. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated on arotary evaporator to provide 100 mg (74% recovery) of zolmitriptan.

EXAMPLE 6 Vaporization of Zolmitriptan

[0116] A solution of 9.8 mg zolmitriptan in 300 μL dichloromethane wasspread out in a thin layer on a 4 cm×9 cm sheet of aluminum foil. Thedichloromethane was allowed to evaporate. The aluminum foil was wrappedaround a 300 watt halogen tube, which was inserted into a glass tubesealed at one end with a rubber stopper. Subjecting the bulb to one 15s, 60 v (variac) treatment afforded volatilized zolmitriptan on theglass tube walls. HPLC analysis of the collected material showed it tobe at least 98% pure zolmitriptan. To obtain higher purity aerosols, onecan coat a lesser amount of drug, yielding a thinner film to heat. Alinear decrease in film thickness is associated with a linear decreasein impurities.

EXAMPLE 7 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Zolmitriptan Aerosol

[0117] A solution of 3.2 mg zolmitriptan in 100 μL methanol was spreadout in a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. Both of the openings of the tubewere left open and the third opening was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within 1 s, an aerosol appearedand was drawn into the 1 L flask by use of the piston, with collectionof the aerosol terminated after 6 s. The aerosol was analyzed byconnecting the 1 L flask to an eight-stage Andersen non-viable cascadeimpactor. Results are shown in table 1. MMAD of the collected aerosolwas 0.7 microns with a geometric standard deviation of 3.3. Also shownin table 1 is the number of particles collected on the various stages ofthe cascade impactor, given by the mass collected on the stage dividedby the mass of a typical particle trapped on that stage. The mass of asingle particle of diameter D is given by the volume of the particle,πD³/6, multiplied by the density of the drug (taken to be 1 g/cm³). Theinhalable aerosol particle density is the sum of the numbers ofparticles collected on impactor stages 3 to 8 divided by the collectionvolume of 1 L, giving an inhalable aerosol particle density of 4.9×10⁷particles/mL. The rate of inhalable aerosol particle formation is thesum of the numbers of particles collected on impactor stages 3 through 8divided by the formation time of 6 s, giving a rate of inhalable aerosolparticle formation of 8.1×10⁹ particles/second. TABLE 1 Determination ofthe characteristics of a zolmitriptan condensation aerosol by cascadeimpaction using an Andersen 8-stage non-viable cascade impactor run at 1cubic foot per minute air flow. Particle size Average particle Masscollected Number of Stage range (microns) size (microns) (mg) particles0  9.0-10.0 9.5 0.00 0 1 5.8-9.0 7.4 0.00 0 2 4.7-5.8  5.25 0.00 0 33.3-4.7 4.0 0.01 2.1 × 10⁵ 4 2.1-3.3 2.7 0.03 2.9 × 10⁶ 5 1.1-2.1 1.60.12 5.7 × 10⁷ 6 0.7-1.1 0.9 0.10 2.5 × 10⁸ 7 0.4-0.7  0.55 0.05 5.7 ×10⁸ 8   0-0.4 0.2 0.20  4.8 × 10¹⁰

EXAMPLE 8 Drug Mass Density and Rate of Drug Aerosol Formation ofZolmitriptan Aerosol

[0118] A solution of 2.6 mg zolmitriptan in 100 μL methanol was spreadout in a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. Both of the openings of the tubewere left open and the third opening was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within seconds, an aerosolappeared and was drawn into the 1 L flask by use of the piston, withformation of the aerosol terminated after 6 s. The aerosol was allowedto sediment onto the walls of the 1 L flask for approximately 30minutes. The flask was then extracted with acetonitrile and the extractanalyzed by HPLC with detection by light absorption at 225 nm.Comparison with standards containing known amounts of zolmitriptanrevealed that 0.4 mg of >96% pure zolmitriptan had been collected in theflask, resulting in an aerosol drug mass density of 0.4 mg/L. Thealuminum foil upon which the zolmitriptan had previously been coated wasweighed following the experiment. Of the 2.6 mg originally coated on thealuminum, 1.5 mg of the material was found to have aerosolized in the 6s time period, implying a rate of drug aerosol formation of 0.3 mg/s.

EXAMPLE 9 Flash Device for Forming Aerosols

[0119] A high-power flashcube (GE or Sylvania), which can produce300-400 J of energy, was inserted into an anodized aluminum tube. Theflashcube/tube assembly was dipped into an organic solution containing adrug and quickly removed. Evaporation of residual solvent from theassembly was performed by placing it into a vacuum chamber for 30 min.This left a film of drug coated on the exterior surface of the aluminumtube. The flashbulb assembly was electrically connected to two 1.5 Vbatteries and a switch using copper wires and then enclosed in a sealed,glass vial. Ignition of the flashbulb was performed by momentarilyturning on the switch between the flashbulb and batteries. Afterignition, the vial was kept closed for 30 minutes such that particles ofvolatilized drug coagulated and condensed on the inside surface of thevial. Analysis of the aerosol involved rinsing the vial with 5 mL ofacetonitrile and injecting a sample of the organic solution into anHPLC. Rizatriptan aerosol was obtained in 99.2% purity (1.65 mg) usingthis procedure. Zolmitriptan aerosol was obtained in 99.6% purity (0.31mg) using this procedure.

EXAMPLE 10 Delivery of Rizatriptan to a Dog

[0120] Apnea was induced in a dog, which was subsequently exposed to a15 SLPM flow of air containing 950 μg of rizatriptan (condensationaerosol formed by volatilizing triazolam off of a heated, metalsubstrate; MMAD˜1.7) through an endotracheal tube. This corresponded toapproximately a 625 cc volume of inhalation air delivered to the dog.Once the dog had received the triazolam aerosol, an air supply valve wasshut off for 5 s, which simulated a 5 s breath hold. Following the hold,the dog was allowed to exhale through an exhalation filter. Arterialblood samples were taken at defined intervals. HPLC analysis of theblood samples indicated that the Tmax for rizatriptan was about 1minutes, with a concentration of greater than 280 ng/mL reached.

EXAMPLE 11 Comparison of Inhaled, Subcutaneous and Oral Admistration ofRizatriptan in a Dog

[0121] The percent change in cerebral vascular resistance from a 30minute baseline was compared after administration of 1 mg of rizatriptanto a dog using the following delivery routes: inhalation, subcutaneous,and oral. After inhalation administration, the resistance increasedapproximately 60 percent in approximately 1 minute. Subcutaneousadministration produced about a 45 percent increase in resistance inabout 20 minutes. Cerebral vascular resistance essentially did notchange over an 80 minute period after oral administration ofrizatriptan.

[0122] The same study was performed by administering either 3.5 mg or 3mg of rizatriptan to a dog: inhalation (3.5 mg inhaled, ˜110% resistanceincrease in about one minute); subcutaneous (3 mg, ˜60% resistanceincrease over about 30 minutes); and, oral (3 mg, essentially noresistance increase over 80 min.).

1. A method of treating headache or migraine comprising administering atherapeutic amount of a rizatriptan or zolmitriptan condensationaerosol, having an MMAD less than 3 μm and less than 5% rizatriptan orzolmitriptan degradation products, to a patient by inhalation, uponactivation by the patient of the formation of, and delivery of, thecondensation aerosol.
 2. The method of claim 1, wherein saidcondensation aerosol is formed by a. volatilizing rizatriptan orzolmitriptan under conditions effective to produce a heated vapor of therizatriptan or zolmitriptan; and b. condensing the heated vapor of therizatriptan or zolmitriptan to form condensation aerosol particles. 3.The method according to claim 1, wherein the condensation aerosol isformed at a rate greater than 0.5 mg/second.
 4. The method according toclaim 1, wherein said therapeutic amount of rizatriptan condensationaerosol comprises between 1 mg and 20 mg of rizatriptan delivered in asingle inspiration.
 5. The method according to claim 1, wherein saidtherapeutic amount of zolmitriptan condensation aerosol comprisesbetween 0.5 mg and 10 mg of zolmitriptan delivered in a singleinspiration.
 6. The method according to claim 2, wherein saidadministration results in a peak plasma concentration of saidrizatriptan or zolmitriptan in less than 0.1 hours.
 7. The methodaccording to claim 1, wherein at least 50% by weight of the condensationaerosol is amorphous in form.
 8. A method of administering rizatriptanor zolmitriptan to a patient to achieve a peak plasma drug concentrationrapidly, comprising administering to the patient by inhalation anaerosol of rizatriptan or zolmitriptan having less than 5% rizatriptanor zolmitriptan products and an MMAD less than 3 microns wherein thepeak plasma drug concentration is achieved in less than 0.1 hours.
 9. Akit for delivering a drug aerosol comprising: a) a thin coating of arizatriptan or zolmitriptan composition, and b) a device for dispensingsaid thin coating as a condensation aerosol.
 10. The kit of claim 9,wherein the device for dispensing said coating as a condensation aerosolcomprises: (a) a flow through enclosure, (b) contained within theenclosure, a metal substrate with a foil-like surface and having a thincoating of a rizatriptan or zolmitriptan composition formed on thesubstrate surface, (c) a power source that can be activated to heat thesubstrate to a temperature effective to volatilize the rizatriptan orzolmitriptan composition contained in said coating, and (d) inlet andexit portals through which air can be drawn through said device byinhalation, wherein heating the substrate by activation of the powersource is effective to form a rizatriptan or zolmitriptan vaporcontaining less than 5% rizatriptan or zolmitriptan degradationproducts, and drawing air through said chamber is effective to condensethe rizatriptan or zolmitriptan vapor to form aerosol particles whereinthe aerosol has an MMAD of less than 3 microns.
 11. The kit according toclaim 10, wherein the heat for heating the substrate is generated by anexothermic chemical reaction.
 12. The kit according to claim 11, whereinsaid exothermic chemical reaction is oxidation of combustible materials.13. The kit according to claim 10, wherein the heat for heating thesubstrate is generated by passage of current through an electricalresistance element.
 14. The kit according to claim 10, wherein saidsubstrate has a surface area dimensioned to accommodate a therapeuticdose of rizatriptan or zolmitriptan composition in said coating.
 15. Thekit according to claim 9, wherein a peak plasma concentration ofrizatriptan or zolmitriptan is obtained in less than 0.1 hours afterdelivery of condensation aerosol to the pulmonary system.
 16. The kit ofclaim 9, further including instructions for use.